Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that TGFbeta1 expression is upregulated in mouse keratinocytes infected with a v-rasHa retrovirus, although the functional significance of this has not been clear. Here we show that v-rasHa retrovirus transduced primary mouse keratinocytes undergo hyperproliferation followed by a TGFbeta1 dependent G1 growth arrest and senescence. The growth arrest is accompanied by a 15-fold increase in total TGFbeta1 secreted and a fourfold increase in secreted active TGFbeta1. When cultured in the presence of a neutralizing antibody to TGFbeta1, the senescence response is suppressed. Levels of the TGFbeta1 target p15ink4b increase during senescence as does association of this kinase inhibitor with cyclinD/cdk4 complexes. However, p16ink4a, p53 and p19ARF expression also increase during senescence. Genetic analysis shows that TGFbeta1 null and dominant negative TbetaBRII expressing v-rasHa keratinocytes resist the G1 growth arrest and do not senescence. This resistance is associated with low expression of p15ink4b and p16ink4a, constitutive Rb phosphorylation and high levels of cdk4 and cdk2 kinase activity. In contrast, inactivation of TGFbetabeta1 secretion or response does not block the induction of p53 and p19ARF, but the level of p21waf1, a p53 target gene, is reduced in cyclin D/cdk4 and cyclin E/cdk2 complexes. Thus, although multiple senescence pathways are activated in response to a ras oncogene, inactivation of TGFbeta1 secretion or response is sufficient to block the senescence program. Since v-rasHa transduced TGFbeta1-/- keratinocytes form squamous cell carcinomas following skin grafting, these results suggest that in mouse keratinocytes, defects in TGFbeta1 signaling accelerate malignant progression by overcoming oncogene induced replicative senescence.
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PMID:Defects in TGF-beta signaling overcome senescence of mouse keratinocytes expressing v-Ha-ras. 1076 27

We here describe an alternative way to microinjection by which cellular transport of immunoglobulins through surface membranes can be achieved after binding to specific surface receptors either induced or constutively present, or via Fc receptors (Ig-mediated). In this report, the internalisation of two antibodies in two different cellular systems is analysed: the anti-p21ras monoclonal antibody (MoAb) after surface Ig binding on murine placental cells and anti-cdc2 MoAb that binds directly to its surface receptor expressed on the human promyelocytic leukemia cell line HL-60. In both cases, binding and internalisation is followed by Electron Microscopy (EM) and function is assessed by different assays. The first involves abrogation of class II antigen expression induced by Interferon-gamma (IFN-gamma) and 5-Azacytidine (5-AzaC) known to be mediated by activation of the ras pathway. The second involves growth cessation of HL-60 cells after antibody adsorption when a G1-S-specific culture supernatant containing anti-cdc2 activity is employed, whereas no growth hindrance is observed when a G2-M-specific anti-cdc2 MoAb is used. Thus, the antibodies do not follow the lysosyme pathway and do not lose their functional activity. This method may be applied in the future in order to achieve biological or clinical therapies.
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PMID:Adsorptive or by pit formation endocytosis of immunoglobulins without loss of function as potential biotherapeutical application. 1085 46

4-(acylaminomethyl)benzamides were prepared in two steps from 4-aminomethylbenzoic acid and assayed in the NCl's primary anti-cancer screen. Eight out of 34 compounds showed interesting antiproliferative activity. From these compounds, three were selected for further in vivo testing. In addition, all the compounds were tested against farnesyltransferase and the cell cycle regulating enzymes cdc2 kinase and cdc25 phosphatase. The compounds proved inactive in these assays, as were some selected compounds in an assay searching for possible interference with the ras/raf interaction in a yeast two-hybrid system.
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PMID:Synthesis of 4-(acylaminomethyl)benzamides and their evaluation as potential anticancer agents. 1092 99

Curcumin (CCM), a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn, is commonly used as coloring agent in foods, drugs and cosmetics. In this study we report that gavage administration of 200 mg/kg or 600 mg/kg CCM effectively suppressed diethylnitrosamine (DEN)-induced liver inflammation and hyperplasia in rats, as evidenced by histopathological examination. Immunoblotting analysis showed that CCM strongly inhibited DEN-mediated the increased expression of oncogenic p21(ras) and p53 proteins in liver tissues of rats. In cell-cycle-related proteins, CCM selectively reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin E and p34(cdc2), but not Cdk2 or cyclin D1. Moreover, CCM also inhibited the DEN-induced increase of transcriptional factor NF-kappa B. However, CCM failed to affect DEN-induced c-Jun and c-Fos expression. It has become widely recognized that the development of human hepatocellular carcinoma (HCC) is predominantly due to the chronic inflammation by virus, bacteria or chemical. Our results suggest a potential role for CCM in the prevention of HCC.
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PMID:Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. 1103 36

The capability of REF cells transformed by EA + E1B-19 kDa and EA + cHa-ras oncogenes to realize the G1/S cell cycle arrest upon serum starvation was studied. The amount of cyclin-kinase inhibitor protein p27/Kip was shown to increase in both normal and transformed cells. However, the p27/Kip-bound cyclin-kinase complexes of transformed cells were found to be active, implying the functional inactivation of p27/Kip inhibitor. Nevertheless, in contrast to E1A + cHa-ras transformants, E1A + E1B-19 kDa transformants undergo the G1 cell cycle arrest. The G1 cell cycle block correlates with the decrease in cyclinE-Cdk2 activity. Since cyclinE-Cdk2 complexes need Thr-160 phosphorylation of Cdk2 by CAK-kinase for full activity, we have analysed the Cdk-7 associated activity upon serum starvation using gst-Cdk2 as a substrate. Serum starvation did not affect CAK activity either in E1A + cHa-ras or in E1A + E1B-19 kDa transformants. Thus, selective suppression of cyclineE-Cdk2 activity in E1A + E1B-19 kDa transformants upon serum starvation does not arise from the action of cyclin-kinase inhibitors, or from change in CAK activity.
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PMID:[Rat embryo fibroblasts transformed by complementation with oncogenes E1A+E1B-19 and E1A+cHa-ras differ in the ability to realize the G1/S block in serum free media]. 1184 Jul 77

The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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PMID:The prognostic molecular markers in hepatocellular carcinoma. 1204 56

AIM: Assessment of occurrence and possible prognostic significance of c-myc and Ha-ras amplification, p53 deletion and overexpression of cyclin D1, p53 and p21 in papillary thyroid cancer. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tumor tissue from 24 patients were investigated. Dot-blot DNA hybridization was used to detect oncogene amplification or deletion. The expression of oncoproteins was determined by immunohistochemical method. RESULTS: In our samples neither Ha-ras amplification nor p53 deletion were found. Low c-myc amplification (mean: 2.55) occured in 4 cases (17%). p53 protein was detected in 16 samples (66.6%), with p21 expression (chi(2)=7.02, p<0.01) in 6 cases (25%). The p53 expression did not influence the tumor fenotype. Cyclin D1 overexpression was found in 12 cases (50%), it was often associated with p21 expression (chi2=10.1, p<0.001) and in inverse relation to the tumor lymphocytic infiltration (chi(2)=5.35, p<0.05). Increased expression of estrogen receptor was shown in 4 cyclin D1 positive samples (17%). CONCLUSIONS: The p53 detected in our study is likely not to be mutant protein in all cases because its presence was associated with p21 expression that the mutant protein cannot induce and also it did not mean more aggressive tumor phenotype. The connection of cyclin D1 overexpression with the lymphocytic infiltration of the tumor suggests that the increased expression of cyclin D1 means poor prognosis. The coexpression of cyclin D1 and p21 raises the modulative character of the p21 protein, thought to be a tumor suppressor originally, but we find a CDK-independent, estrogen receptor mediated effect of cyclin D1 more likely, which has been described in breast cancer and is also proved by the coexpression of cyclin D1 and estrogen receptor detected here.
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PMID:[Investigation of oncogene amplification or deletion, and oncoprotein expression in papillary thyroid cancer] 1205 Jun 91

Phosphorylation of linker histone H1(S)-3 (previously named H1b) and core histone H3 is elevated in mouse fibroblasts transformed with oncogenes or constitutively active mitogen-activated protein kinase (MAPK) kinase (MEK). H1(S)-3 phosphorylation is the only histone modification known to be dependent upon transcription and replication. Our results show that the increased amounts of phosphorylated H1(S)-3 in the oncogene Ha-ras-transformed mouse fibroblasts was a consequence of an elevated Cdk2 activity rather than the reduced activity of a H1 phosphatase, which our studies suggest is PP1. Induction of oncogenic ras expression results in an increase in H1(S)-3 and H3 phosphorylation. However, in contrast to the phosphorylation of H3, which occurred immediately following the onset of Ras expression, there was a lag of several hours before H1(S)-3 phosphorylation levels increased. We found that there was a transient increase in the levels of p21(cip1), which inhibited the H1 kinase activity of Cdk2. Cdk2 activity and H1(S)-3 phosphorylated levels increased after p21(cip1) levels declined. Our studies suggest that persistent activation of the Ras-MAPK signal transduction pathway in oncogene-transformed cells results in deregulated activity of kinases phosphorylating H3 and H1(S)-3 associated with transcribed genes. The chromatin remodelling actions of these modified histones may result in aberrant gene expression.
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PMID:Histone H1(S)-3 phosphorylation in Ha-ras oncogene-transformed mouse fibroblasts. 1246 60

Deregulation of the retinoblastoma (pRB) tumor suppressor pathway and telomerase activation have been identified as rate-limiting steps for immortalization of primary human epithelial cells. However, additional molecular aberrations including p53 inactivation, ras activation, and deregulation of protein phosphatase 2A activity are necessary for full transformation of immortalized epithelial cells. Genomic instability is observed in most human tumors and constitutes an important mechanism to allow emerging tumor cells to acquire additional mutations to efficiently overcome selection barriers during carcinogenic progression. In an attempt to model oral cancer in a human cell-based system, we analyzed normal oral epithelial keratinocytes with the pRB pathway dysregulated by loss of expression of the cyclin-dependent kinase (cdk) 4/cdk6 inhibitor p16(INK4A) and/or ectopic expression of cdk4 or expression of the human papillomavirus (HPV) type 16 E7 oncoprotein. Ectopic expression of cdk4 and HPV-16 E7 was equally efficient in extending the life span of normal oral keratinocytes, and each was able to cooperate with telomerase (hTERT) to immortalize these cells. HPV-16 E7/hTERT-immortalized normal oral keratinocytes showed centrosome abnormalities, whereas populations of cdk4/hTERT-immortalized cells or hTERT-immortalized cells that had lost expression of p16INK4A showed no such abnormalities. These results demonstrate that disruption of the p16INK4A/pRB checkpoint of epithelial cell immortalization does not necessarily lead to centrosome-associated genomic instability.
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PMID:Abrogation of the retinoblastoma tumor suppressor checkpoint during keratinocyte immortalization is not sufficient for induction of centrosome-mediated genomic instability. 1254 5

HR12 is a novel farnesyltransferase inhibitor (FTI). We have shown previously that HR12 induces phenotypic reversion of H-rasV12-transformed Rat1 (Rat1/ras) fibroblasts. This reversion was characterized by formation of cell-cell contacts, focal adhesions and stress fibers. Here we show that HR12 inhibits anchorage independent and dependent growth of Rat1/ras cells. HR12 also suppresses motility and proliferation of Rat1/ras cells, in a wound healing assay. Rat1 fibroblasts transformed with myristoylated H-rasV12 (Rat1/myr-ras) were resistant to HR12. Thus, the effects of HR12 are due to the inhibition of farnesylation of Ras. Cell growth of Rat1/ras cells was arrested at the G1 phase of the cell cycle. Analysis of cell cycle components showed that HR12 treatment of Rat1/ras cells led to elevated cellular levels of the cyclin-dependent kinase inhibitor p27Kip1 and inhibition of the kinase activity of the cyclin E/Cdk2 complex. This is the first time an FTI has been shown to lead to a rise in p27Kip1 levels in ras-transformed cells. The data suggest a new mechanism for FTI action, whereby in ras-transformed cells, the FTI causes an increase in p27Kip1 levels, which in turn inhibit cyclin E/Cdk2 activity, leading to G1 arrest.
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PMID:The inhibition of Ras farnesylation leads to an increase in p27Kip1 and G1 cell cycle arrest. 1282 46


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